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Neuroprotective therapies for multiple sclerosis and other demyelinating diseases

Neuroprotective therapies for multiple sclerosis and other demyelinating diseases Damage to the Central Nervous Systems (CNS) in Multiple Sclerosis (MS) seems to be mainly due to chronic inflammation of the CNS with superimposed bouts of inflammatory activity by the adaptive immune system. The immune mediated damage can be amplified by neurodegenerative mechanisms in damaged axons including anterograde or retrograde axonal or transynaptic degeneration, synaptic pruning and neuronal or oligodendrocyte death. As such, it is highly unlikely that CNS damage can be prevented using only immunomodulatory drugs. For this reason, neuroprotection, aimed at preventing axonal, neuronal, myelin, and oligodendrocyte damage and cell death in the presence of this toxic microenvironment is highly pursued in MS and other demyelinating diseases. Neuroprotective strategies target different processes including oxidative stress, ionic imbalance (sodium, potassium or calcium), energy depletion, trophic factor support, metabolites balance, excitotoxicity, apoptosis, remyelination, etc. Although none of these strategies have translated into approved drugs to date, improvement in the understanding of underlying biology, in the design of clinical trials specific for assessing neuroprotection, and new technologies for developing novel therapies for neuroprotection suggest a new avenue for treating MS, Optic Neuritis or Neuromyelitis Optica (NMO). Several of these therapies are now entering clinical phases and if successful, such strategies would improve patients’ quality of life, and will be even more critical for patients with progressive MS. In the event that such therapies target natural repair mechanisms rather than disease specific processes, they can potentially be useful for other brain diseases such as stroke, neurodegenerative diseases, brain trauma or epilepsy. Keywords: Multiple sclerosis, Neuromyelitis optica, Demyelinating diseases, Neuroprotection, Trophic factors, Axonal damage, Remyelination Background there are significant limitations for promoting neuronal The central nervous system is highly sensitive to damage: network regeneration in adults after damage (e.g. presence the role of neuroprotection of axonal growth inhibitory molecules such as neurite The Central Nervous System (CNS) is especially sensi- outgrowth inhibitor A (Nogo-A)). Nevertheless, even if tive to damage compared to other tissues because of its regenerative therapy for the CNS is highly sought after, an highly specialized structure and function; it is composed intermediate, longer-term promising alternative approach of billions of neurons making both long and short-range is neuroprotection [3]. connections, requires high energy and metabolite con- After insults such as ischemia, inflammation or excito- sumption, and has significant post-damage repair restric- toxicity, neurons and axons may suffer significant damage, tions. Brain connections are made in a highly complex resulting in oxidative damage of DNA and proteins, and synchronized process during development and are reduced energy production, imbalance of ionic homeosta- refined with training [1]. Once defined, brain connectiv- sis and ion channel functioning, endoplasmic reticulum ity is fixed by myelination and other processes in order impairment and protein folding degradation or micro- to preserve memory and function [1, 2]. For this reason, tubule mediated axonal transport impairment. Due to the high level energetic and functional requirements that Correspondence: pvilloslada@clinic.ub.es neurons have for maintaining long-distance nerve conduc- Center of Neuroimmunology, Institut d’Investigacions Biomèdiques August tion (with axons up to 0.5 m long in the corticospinal Pi i Sunyer (IDIBAPS), Centre Cellex 3A, Casanova 145, Barcelona 08036, Spain Department of Neurology, University of California, San Francisco, USA © 2016 Villoslada. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Villoslada Multiple Sclerosis and Demyelinating Disorders (2016) 1:1 Page 2 of 11 tract), neuronal malfunction can trigger self-destruction the release of trophic factors, suppressing local inflamma- processes such as apoptosis, autophagia, synaptic pruning tion or promoting a microenvironment supporting the and many other forms of neuronal cell death [4–6]. survival of neurons, axons and oligodendrocytes [12]. Furthermore, damaged axons can trigger an active process Finally, secondary neuroprotection can be achieved by the of axonal degeneration regulated by levels of nicotinamide reduction of the insult such as restoring blood supply in adenine dinucleotide (NAD). Axonal degeneration is a ischemia, decreasing excitotoxicity by reducing epilepto- process different from apoptosis, which results in acute genic activity in seizures or decreasing CNS inflammation axonal transection and chronic anterograde (Wallerian) or with the use of immunomodulatory drugs (e.g. glatiramer retrograde degeneration. This process is regulated by acetate, fingolimod, dimethyl-fumarate or laquinimod) in several key molecules such as nicotinamide nucleotide the case of MS [13–16]. adenylyltransferase 2 (NMNAT2), Sterile Alpha And TIR Table 1 displays a list of several therapeutic strategies Motif Containing 1 (Sarm1) and phosphate starvation being pursued for neuroprotection. In the pursuit for response 1 (PHR1) which regulates levels of NAD, or neuroprotective strategies, trophic factors are proposed downstream steps regulated by c-Jun N-terminal kinases as the Holy Grail [17, 18]. Rather than coding for all (JNK), glycogen synthase kinase 3 (GSK3) or inhibitor of neuronal connections during development, evolution kappa B kinase (IKK) converging in mitochondria and developed the trophic factor strategy, which regulates energy dysfunction and calpains activation leading to neuronal survival and connection maintenance with the calcium imbalance [7, 8]. Additionally, myelin is highly release of trophic factors from the target cell to the susceptible to damage in the white matter because oligo- projecting neuron. For this reason, trophic factors dendrocytes are also high-energy demanding cells (myelin activate a set of signaling pathways in neurons, such as turn-over is around one month) but the blood supply Phosphoinositide 3-kinase (PI3K), Mitogen-activated prioritizes grey over white matter [6]. Moreover, lipid protein kinase kinase (MAPKK), Nuclear factor-κB structures such as myelin are highly susceptible to damage (NFKB) and others that stop apoptosis, promote cell by immune mediators and oxidative stress [9]. In this survival and differentiation and trigger other beneficial context, inflammatory, ischemic or degenerative insults effects such as decreasing oxidative stress, regulating can induce either direct damage of the neurons (e.g. ne- ion channels, etc. [19]. Several growth factors have been crosis) or delayed degenerative processes that are triggered tested in animal models or clinical trials including neu- once surviving neurons identify they can no longer rotrophins (nerve growth factor, brain-derived nerve maintain their function and initiate different forms of cell factor, neurotrophin-3), insulin-growth factor (IGF-1), death, axonal degeneration or synaptic pruning [10]. neurocytokines (cilliary-neurotrophic factor, leukemia Another feature to take into account when managing inhibitor factor, interleukin-6), and glial-derived nerve neurological damage is the plastic and redundant nature factor family (erythropoietin, etc.) [20, 21]. They were of the CNS, which explain why damage of many CNS tested in trials of peripheral neuropathy (diabetes or regions are not eloquent at the clinical level. This implies adquired immunodeficiency syndrome) or neurodegen- that CNS damage need to surpasse a given threshold of erative diseases (Alzheimer disease, Parkinson disease, damage in order to translate to clinical symptoms, which Huntington disease, Amyotrophic Lateral Sclerosis (ALS)) prevents close monitoring of CNS damage by clinical using human recombinant proteins delivered intraven- assessment and cause delayed diagnosis or disability moni- ously, intrathecaly or using engineered cells or gene ther- toring. All these facts, including sensitivity of neural apy vectors [22–25]. Lack of success to date for the use of networks to damage, poor regenerative ability, and late trophic factors to prevent CNS damage does not preclude diagnosis of CNS damage, support neuroprotection as an the usefulness of trophic factors as a therapeutic target. important therapeutic strategy for decreasing the burden Lack of efficacy was attributed to poor pharmacological of neurological diseases. properties of the recombinant proteins to enter the CNS and reach the target neurons, inadequate clinical trial de- Neuroprotective strategies sign, such as testing patients in late stages when neuronal Almost every mechanism of damage identified in brain death is massive and using insensitive clinical or imaging diseases has been proposed as a therapeutic target for outcomes, or side effects that limited dosing and patient neuroprotection (Fig. 1). Several biological processes exposition [26, 27]. However, the trophic factor pathways specific to the CNS (e.g. trophic factor signaling, axonal are at the core of cellular processes promoting neuronal guidance, myelin formation) or critical for neurons (e.g. and oligodendrocyte survival and for this reason are worth apoptosis, energetic supply, ionic balance) have been pursuing to see if activation of these pathways using differ- mimicked with experimental therapies [3, 11]. In addition, ent strategies might prevent permanent CNS damage. several regenerative therapies, such as stem cells, may pro- Energy depletion and mitochondria dysfunction are vide some benefits via neuroprotective effects, including another key factor in promoting neuronal degeneration Villoslada Multiple Sclerosis and Demyelinating Disorders (2016) 1:1 Page 3 of 11 Fig. 1 Proposed targets for neuroprotective therapies. The pathways involved in neuroprotection include 1) Active axonal degeneration pathway activation (mediated by depletion of NAD levels by NMNAT2, PHR1 and Sarm1 activation); 2) trophic factor signaling (PI3K, MAPKK, NFkB); 3) oxidative stress (induced by inflammatory cells and mitochondria dysfunction); 4) energy depletion (due to mitochondria impairment and increased demand from Ca channels); 5) axonal transport blockade (failing to deliver mitochondria, signaling and molecular complexes to soma, nodes of Ranvier or synpasis); 6) ionic imbalance (due to ion channel redistribution and changes in activity, leading to increase of intracellular calcium); 7) Excitotoxicity (mediated by excess of glutamate signaling through the NMDA receptors); 8) remyelination (from OPC repopulation of demyelinated areas to myelination of denuded axons by mature oligodendrocytes (OG), which provide metabolic support to the axon (NAA or PC); 9) protective effects of astrocytes (providing trophic factors such as IGF-1 or BDNF, metabolic substrates such as lactate, or pro-survival signals such as CD200-CD200L) and M2 microglia (with scavenger and tissue healing activity) Table 1 Molecules and pathways targeted in neuroprotection Pathway Molecule Candidate drugs Trophic factors BDNF, IGF-1, CNTF, etc. rhBNDF, rhIGF-1, rhCNTF, etc., CERE-110 (AAV2-NGF) Mitochondria dysfunction and Cytochrome C, ATP Resveratrol, Rosiglitazone, Pioglitazone, Troglitazone, energy depletion Bezafibrate (PPARγ activator) Ion channel Sodium, Potassium or Calcium channels, Phenitoin, Lamotrigin, Amiloride Acid-Sensing Ion Channels Oxidative stress iNOS, Nerf2 Dimethyl-Fumarate, Resveratrol, Vitamin E, Vitamin C, Melatonin, Carnosine, Coenzyme-Q, Idebenone, Carotenoids Excitotoxicity Glutamate Memantine, Riluzole Demyelination MOG, Lingo-1 BIIB003, Clemastine benztropine, miconazole and clobetasol Axonal transport Dynamin, kinesin, microtubules Epothilone B Inhibitory molecules axonal growth Lingo-1, Nogo-A BIIB003, GSK1223249 and myelination Apoptosis Bcl2, Bim, Bax, Cytochrome C, Caspase-3 Caspase or calpain inhibitors, Mynocycline Microglia M2 mediated neuroprotection CD200, trophic factors (BDNF), Interferon-beta, Glatiramer acetate, Fumarate, anti-inflammatory cytokines (IL-4, IL-10, TGFß) Dimethyl-Fumarate, Mesenchymal stem cells Astrocyte mediated neuroprotection Trophic factors, NAA, pyruvate, lactate Pentamidine, Methylthioadenosine, Fingolimod BDNF brain-derived nerve factor, IGF-1 insulin growth factor, CNTF cilliary neurotrophic factor, NGF Nerve growth factor, rh recombinant human, iNOS inducible nitric oxide synthase, ATP adenosine triphosphate, MOG myelin oligodendrocyte glycoprotein, NAA N-Acetyl aspartate Villoslada Multiple Sclerosis and Demyelinating Disorders (2016) 1:1 Page 4 of 11 [4, 28, 29]. The CNS consumes 20 % of the overall to modulate without inducing further damage. However, oxygen and energy of the body and neurons require the several approved therapies reduce oxidative stress in- support of astrocytes for maintaining their metabolic duced by the insult such as the immunomodulatory drug activity [6]. Neurons use lactate as a substrate for the dimethyl-fumarate (through activation of nuclear factor Krebs cycle, which is provided by astrocytes. Neurons (erythroid-derived 2)-like 2 (Nerf2)) [39], and mesenchy- are very sensitive to adenosine triphosphate (ATP) de- mal stem cells [40], which decrease reactive oxygen pletion and mitochondrial damage due to their high- species induced by inflammation. energy consumption needed to maintain the intensive Excitotoxicity is postulated as the prime mechanism of protein systems supporting their connections as well as damage in epilepsy and it has also been associated with the ion channels in charge of maintaining the electrical neurodegenerative diseases as well with MS [41, 42]. By impulse. This is particularly true for axons, because they over-activating the excitatory glutamate receptors, neu- are long and tiny structures receiving support from the rons experience high levels of electrical and energetic soma as well as from the axon-myelin unit [4]. Energy activity, inducing ion imbalance and promoting neuronal depletion, mitochondria function impairment and axonal death. Although there is clear evidence about the role of transport deficits are common in CNS diseases and for this process in animal models, its involvement in MS this reason targeting energy supply to the CNS has and other brain diseases has not been clarified in detail. been pursued as well. Studies began by providing add- Riluzole is an approved drug inhibiting N-methyl-D- itional sugar supplies or decreasing metabolic rate (e.g. aspartate (NMDA) receptors, in addition to modulat- hypothermia) but now other strategies such as adminis- ing sodium channels, but its efficacy in ALS is modest tering metabolite precursors, or preserving mitochon- and trials in MS failed to show benefits [43]. Memantine dria functioning have also been tested in trials [29–31]. is approved for Alzheimer’s disease and was shown to There is now a strong interest in understanding the modulate glutamate excitatory activation [44], but it was early molecular events in mitochondria damage during found to transiently worsen symptoms in patients with neuronal and axonal damage in order to prevent ener- MS, reproducing pseudoexacerbations [45, 46]. getic failure [4, 7, 32]. Demyelination is the most prominent feature in MS. Ion channels are key for neuronal homeostasis and for Promoting myelin recovery through remyelination is a maintaining the electrical impulse. Due to the highly natural strategy for treating demyelinating diseases. It is specialized neuronal design, ion channel activity is highly important to keep in mind that myelin is one of the prominent in the axonal initial segment as well as at the most important elements for protecting axons, the node of Ranvier [33]. This creates specific sites where myelin-axon unit [9]. Myelin is active not only in pro- ion fluxes are modulated and energy is required for axon moting saltatory conduction (which increases electrical functioning. Ion channel modulators have been explored conduction speed and reduces energy needs), but also as neuroprotective therapies in addition to their known in providing metabolic support to axons (e.g. N-Acetyl- beneficial effects in epilepsy or pain, including sodium Aspartate (NAA), phosphatidylcholine (PC), etc.) [47]. channel modulators phenytoin, carbamacepin, lamotri- For this reason, preventing demyelination and promot- gine, amiloride; and potassium channel modulators, ing remyelination is one of the most important neuro- aminopyridine or diazoxide (Table 2) [33]. Although protective strategies for MS [48]. There are several benefits has been observed in animal models and drugs being tested at present to promote remyelination small clinical trials, the challenge is determining how by blocking leucine rich repeat and immunoglobin-like to maintain their beneficial effects in the long-term domain-containing protein 1 (Lingo-1) using anti-Lingo-1 and understanding to which degree their effects are monoclonal antibody, or repurposing drugs such as clem- just maintaining the electrical impulse (symptomatic astine or guanabenz (Table 2). The main challenge will be effects) versus promoting long-term neuronal or axonal to probe in humans whether such drugs are able to induce survival (neuroprotection effects) [34]. remyelination of the CNS and whether this biological Oxidative stress is another hot topic in neuroprotec- activity translates to clinical benefits. Quantifying demye- tion [35]. The concept that free radicals degrade DNA lination and remyelination in the living human CNS still and proteins suggest that anti-oxidative strategies would remains a challenge at the clinical level due to techno- prevent cell death. There is ample evidence of the pres- logical limitations (e.g. lack of specificity of MRI se- ence of increased oxidative stress in the damaged CNS quences such as magnetic transfer ratio) [49]. in MS, neurodegenerative diseases, stroke and epilepsy Axonal transport is a key process in the homeostasis [36–38]. However, oxidation in mitochondria and other of neurons and their long connections. Axons need to organelles is a complex process required for energy transport to the synapsis most of the protein synthesis production and other metabolic activities (e.g. signaling machinery as well as providing energy supply to the by nitric oxide (NO)) and for this reason is very difficult nodes of Ranvier and synapsis. In addition trophic factor Villoslada Multiple Sclerosis and Demyelinating Disorders (2016) 1:1 Page 5 of 11 Table 2 Neuroprotective drugs in clinical development for MS Drug Company Type of compound MoA summary Route of Phase CT.org administration KPT-350 Karyopharm Therapeutic Small molecule - Selective Inhibitor Antioxidant Neuroprotection Oral Preclinical N/A of Nuclear Export (SINE) NDC-1308 ENDECE Neural Small molecule Estradiol analog Neuroprotection Remyelination N/A Preclinical N/A Methylthioadenosine Digna Biotech Metabolite Methyltransferases modulator Neuroprotection Oral Preclinical N/A Remyelination NRP2945 CuroNZ Peptide Neuroprotection N/A Preclinical N/A ER agonist Karo Bio AB Smal chemicals Estrogen Receptor beta agonist Neuroprotection N/A Preclinical N/A VX15/2503 Vaccinex mAb - anti-semaphorin 4D Anti-SEMA4D Neuroprotection Remyelination Intravenous Phase 1 NCT01764737 RNS60 Revalesio Physically-Modified Saline Immunomodulation Neuroprotection Intravenous Phase 2 NCT01714089 GNbAC1 GeNeuro mAb First-in-Class Immunomodulation Remyelination Intravenous Phase 2a NCT01639300 TRO19622 Olesoxime Trophos SA Small chemical Antioxidant Oral Phase 1 NCT01808885 BIIB0033 - Anti-LINGO1 Biogen Idec mAb LINGO-1 antagonist Remyelination Intravenous Phase 2 NCT01864148 Neuroprotection Phase 2 NCT01721161 rHIgM22 Acorda Therapeutics mAb - Recombinant human IgM Remyelination Intravenous Phase 1 NCT01803867 MN-166 Ibudilast MediciNova Small molecule Immunomodulation Neuroprotection Oral Phase 2 NCT01982942 RGN-352 RegeneRx Peptide Neuroprotection Remyelination N/A N/A N/A EGCG - Epigallocatechin-gallate Generic Green tea extract (Polyphenon E) Anti-oxidant Oral Phase 2 NCT00525668 NCT01451723 Lamotrigine GlaxoSmithKline Small chemical Sodium channel modulator Neuroprotection Oral Oral NCT01879527 Phenitoin Generic Small chemical Sodium channel modulator Neuroprotection Oral Phase 2 NCT01451593 MRF-008 Guanabenz Myelin Repair Small chemical Alpha agonist of the alpha-2 adrenergic receptor Oral Phase 1 NCT02423083 Foundation Remyelination Clemastine Generic Small chemical Remyelination Oral Phase 2 NCT02040298 BAF312 Novartis Small chemical - Siponimod S1P1 antagonist Neuroprotection Oral Phase 2 NCT00879658 RRMS Phase 3 SPMS Amiloride Generic Small chemical Sodium channel modulator Oral Phase 2 NCT01910259 BN201 Bionure Small chemical Neurotrophin agonist Neuroprotection Intravenous Phase 1 N/A Erythropietin Generic Human recombinant protein Trophic factor Neuroprotection Intravenous Phase 3 NCT01962571 GSK1223249 – Ozanezumab GlaxoSmithKline mAb Anti-Nogo-A Axonal regeneration Intravenous Phase 2 NCT01435993 Diazoxide Generic Small chemical Potassium channel opener & mitochondrial Oral Phase 2 NCT01428726 channel modulator Minocycline Generic Small chemical Anti-apoptotic & anti-oxidant Oral Phase 2 NCT01073813 Riluzole Generic Small chemical Sodium channel and NMDA modulator Oral Phase 2 NCT00501943 Villoslada Multiple Sclerosis and Demyelinating Disorders (2016) 1:1 Page 6 of 11 Table 2 Neuroprotective drugs in clinical development for MS (Continued) MD1003 - Biotin Generic Vitamin Carboxylases coenzyme (acetylCoA carboxylase) Oral Phase 3 NCT02220933 Remyelination BG12 - Dimethyl Fumarate Biogen Idec Metabolite Anti-oxidant hydroxycarboxylic acid receptor 2 Oral Approved NCT00420212 agonist FTY720 - Fingolimod Novartis Small chemical S1P1 and S1P5 antagonist neuroprotection Oral Approved NCT00355134 Villoslada Multiple Sclerosis and Demyelinating Disorders (2016) 1:1 Page 7 of 11 transportation (e.g. brain-derived neurotrophic factor also termed M2, is associated with suppressing inflam- (BDNF)) from synapsis to the soma is also critical for mation and the creation of a supportive microenviron- neuronal survival [29]. This requires efficient transport ment supporting neuronal survival [12]. Furthermore, through the axons based on intraxonal fluxes but mainly astrocytes, as the main supporters of neuronal function, driven by microtubules transporting organelles to and display a wide array of positive functions for promoting from the soma using the dynein and kinesin systems re- neuronal survival. Moreover, stem cell therapy may show spectively. Such molecular transporters are very sensitive beneficial effects above and beyond just replacing cells to protein denaturation, lack of energy, inflammation by creating a supportive microenvironment and suppress- and other types of damage [32, 50]. Also, it is known ing inflammation [12, 40]. Identification of the different that mitochondria accumulate in the nodes of Ranvier mechanisms involved will provide new targets for devel- (stationary sites) in order to provide extra ATP to sites oping neuroprotective strategies. rich in ion channels, and they are also transported to synapses to provide energy and are retrogradely trans- Unmet needs for neuroprotection in MS and ported for degradation. Inflammation, ischemia and other demyelinating diseases processes severely impair axonal transportation, including In MS, CNS damage is produced by a complex inflam- mitochondria delivery at nodes of Ranvier, contributing matory process. Although in the past it was believed that to energy and metabolite depletion and axonal damage in the relapsing-remitting phase CNS damage was due [32, 51]. Recently, it has been shown that tubuline tar- only to the presence of inflammatory infiltrates within geting drugs may preserve microtubule function and the MS plaques, in the last decade it has been clearly protect axons from degradation in models of spinal shown that MS is a diffuse disease with inflammation, cord injury [52]. In addition, neurofilaments are in demyelination and axonal loss both in the grey and charge of keeping the 3D axonal structure and after white matter [58, 59]. This diffuse inflammation, also damage, neurofilaments become hyperphosphorylated, termed trapped inflammation, is mainly drive by activated losing their function and inducing the collapse of axons microglia, although cells of the adaptive immune system [53]. Therefore, preserving axonal structure and function may be also present. Therefore, myelin and axons are is an important strategy for promoting neuroprotection. acutely damaged by inflammatory infiltrates and chronic- For more than a century, since Cajal seminal studies, ally damaged by chronic microglia activation; both pro- it has been known that the brain inhibits axonal regrowth, cesses being present in relapsing and progressive MS to which prevents CNS regeneration. The identification that different extent and dynamics [36]. However, in progres- myelin was the main inhibitor of axonal growth was sive MS, relapses due to new inflammatory infiltrates tend followed by the identification of several proteins such as to decrease or disappear because less tissue is available for Lingo-1 and Nogo-A that prevent axonal growth signaling damage. Also, in parallel to the inflammatory process, NGF through the nerve growth factor (NGF) receptor p75 axonal degeneration takes place in CNS areas already receptor [54]. This mechanism is important for avoiding damaged long time ago because of the lack of myelin the formation of aberrant connections and preserving support, presence of an aggressive microenvironment, brain connectivity, at the cost of decreasing the regenera- retrograde axonal degeneration or transynaptic degener- tive capacity of the CNS. The discovery of the molecules ation [60]. Moreover, after one decade of damage and responsible for such processes has been followed by the recovery during the relapsing-remittig phase, oligodendro- development of monoclonal antibodies (mAb) targeting cytes fail to produce new myelin and ultimately die; with these pathways in order to promote axonal regeneration. time, the capacity of oligodendrocyte precursors to replace There are several clinical trials in MS testing such ap- lost oligodendrocytes also decreases, leading to large areas proaches including the use of mAb against Lingo-1 and of demyelination [61]. In this scenario, it is clear that MS Nogo-A (Table 2). The main concern is the pharmaco- patients require therapies aimed at stopping the degenera- logical restrictions that mAb has in order to reach high tive process and preventing new CNS damage, on top of levels in the CNS as well as the timing for this therapeutic the immunomodulatory strategy aimed at preventing intervention after injury. inflammation [62]. Finally, it is well known that glia, including astrocytes Current immunomodulatory drugs are not completely and microglia, can display neuroprotective activities, effective and drugs with high efficacy may induce severe although many of them are poorly understood [12, 55]. adverse-events. We must also take into account patient For example, healthy neurons express CD200, which heterogeneity as well as the difficulty for predicting interacts with CD200L promoting survival signals [56]. disease activity at the time of defining the immunomod- Also, both microglia and astrocytes can release trophic ulatory therapy. For this reason, at present is not factors and provide metabolic support to neuronal func- possible to guarantee that treated patients are going to tion [57]. The neuroprotective phenotype of microglia, be free of disease activity and CNS damage induced by Villoslada Multiple Sclerosis and Demyelinating Disorders (2016) 1:1 Page 8 of 11 the autoimmune attack. And even in the best scenario, humans with remyelinating potential [68] and it is now be- damaged tissue is still at risk of developing degenerative ing tested in clinical trials in MS patients (NCT01803867, processes in the long-term. Considering that regenera- NCT02398461). Regarding small chemicals, two approved tive therapies are still far from being applied in clinical drugs that are being explored for their effect on remyelina- practice, protecting the brain against chronic inflamma- tion are clemastine and guanabenz after having shown a tion (not significantly modulated by current immunother- remyelinating effect in vitro and animal models [69]. apy), and preventing neurodegeneration in the long-term, Other strategies in clinical phases include the use of is being pursued as the main strategy in the medium term trophic factor compounds (eritropoietin, BN201), anti- for decreasing disability accumulation in patients with oxidant compounds (the green tea extract epigallocatechin- MS. This is true both for patients with relapsing MS as 3-gallate, ginkgo biloba extracts, biotin, dimethyl-fumarate, well as in the case of patients with progressive MS, in olexosime), modulating estrogen receptors, metabo- which inflammation is still present until the end and lites (dimethyl-fumarate, methyltioadenosine), blocking degenerative processes [55, 59]. semaphorins (VX15/2503), and ion channels modula- In the case of other demyelinating diseases such as tors (carbamacepin, phenytoin, lamotrigin, amiloride, NMO, the need for neuroprotection is also present but riluzole) (Table 2) [21, 70]. All these drugs still need for different reasons [63]. In NMO there is no evidence to show their efficacy in phase 3 trials and then define of progressive course of the disease or presence of how they would be integrated in the MS armamentarium, chronic trapped inflammation in the CNS. For this probably as a combination therapy with immunomodula- reason, all CNS damage and clinical disability observed tors for relapsing MS or perhaps in combination with in NMO is attributed to the damage induced during different agents for progressive MS. acute relapses, which are significantly more tissue destruc- In addition to drugs being tested as neuroprotectants, tive than in MS [64]. The necrotic characteristic of the we must also consider stem cells as another approach NMO lesions has parallelism with stroke-induced damage, to neuroprotection in MS [71]. At present, the most a prototypic model for neuroprotection in which is critical tested stem cells are mesenchymal stem cells, which preventing severe CNS damage in order to reduce disabil- have shown immunomodulatory and neuroprotective ity. The good news is that the inflammatory-induced properties in vitro and in animal models [72]. Recent damage in NMO may operate over longer periods of trials in patients with relapsing and progressive MS time than brain ischemia, providing a wider therapeutic have shown some beneficial effects in terms of decreasing window for intervention (from minutes to days). Recur- relapse rate or disability [73–75], but without clarifying rent Idiopatic Optic Neuritis, Relapsing Optic Neuritis whether these effects are due to its immunomodulatory or or Transverse Myelitis are also other less common neuroprotective effects. A large multicentric randomized types of demyelinating diseases that would follow the trial (MESEMS trial; NCT02403947) is ongoing to evalu- NMO paradigm for neuroprotection, decreasing CNS ate its efficacy in MS. In addition, phase 1 and 2 trials are damage due to relapses. ongoing or being planned to test the efficacy of other stem cells such as oligodendrocyte or olfactory ensheeting glial Neuroprotective therapies under development for cells and probably neural cells in the near future. MS and other demyelinating diseases Neuroprotection is a well-accepted concept in the thera- Challenges for developing neuroprotective peutic strategy of neurologists, but in order to be useful therapies at the clinical level, efficacy must be demonstrated in Lack of approved neuroprotective drugs is due to both randomized clinical trials [65, 66]. At present there is a poor understanding of the mechanisms of damage and growing list of new drugs and repurposing of drugs the low recovery ability of the CNS (as discussed above) being tested from phase 1 to phase 3 trials (Table 2). as well as the limitations of clinical trials for probing the One of the most active areas of research are remyelinat- efficacy of such drugs. First, probing the efficacy of a ing therapies, which can be categorized either as regenera- neuroprotective drug requires selecting the right indica- tive therapy (aimed to restore myelin) or neuroprotective tion, stage of the disease and group of patients in which therapy (aimed to protect axons and restore nerve con- such intervention can translate to a biological benefit as duction) [67]. A recent trial testing the mAb blocking well as to a clinical benefit. For example, treating pa- Lingo-1 (BIIB033) has shown improvement in the laten- tients in the very late stages of the disease, when damage cies of the visual evoked potentials in patients with optic of the CNS is very severe and few neurons and axons neuritis, suggesting an improvement of nerve conduction can be rescued, may not translate to clinical benefits. typically associated with remyelination (NCT01721161). This late diagnosis is one of the greatest limitations to date Another mAb promoting remyelination is rHIgM22, which in other neurodegenerative diseases such as Alzheimer or was discovered as part of the natural antibody repertoire in Parkinson disease and probably in progressive MS. Villoslada Multiple Sclerosis and Demyelinating Disorders (2016) 1:1 Page 9 of 11 Second, pharmacological properties of the drug should Conclusions be good enough to be sure to deliver the signal in the Relapsing MS and other demyelinating diseases have right site of the CNS and with enough intensity to ob- benefited significantly from the advancements of new tain positive outcomes. This is one of the limitations of immunomodulatory therapies, but the challenge of mAb, stem cells and some other drugs. Also, dose selec- protecting CNS from damage remains one of the top tion and defining the therapeutic window based in priorities for all demyelinating diseases as well as efficacy-toxicity balance as well as in the timing of the neurodegenerative diseases or acute brain damage by intervention from the onset of damage is critical as well. trauma or stroke. Novel discoveries in neurobiology Previous studies with recombinant trophic factors may provide new therapeutic targets, and new imaging modal- have failed because poor pharmacokinetic properties as ities provide the opportunity to evaluate the efficacy of well as toxicity of the recombinant proteins prevented these new neuroprotective drugs. Because several of the the use of efficacious doses [27]. Also, we must keep in mechanisms being targeted by neuroprotective therapies mind that patients with MS are young and the disease are common between diseases, some of the biomarkers evolves slowly over years, and for this reason MS patients and therapeutics strategies may be useful for different type are not likely to accept the risk of side-effects. of diseases, although medicine use to tell us that any Third, biomarkers are envisioned as a key strategy for single therapeutic approach fitting all CNS diseases is moving new drugs from preclinical stages to phase 1 highly unlikely. and 2 trials, helping to select the best therapeutic regi- We will hopefully soon have effective neuroprotective men and dose, identify the best patient subgroups to be therapies ready to use in patients, which combined with tested (avoiding non-responders) and match surrogate immunomodulatory drugs, will help to prevent CNS with clinical endpoints in order to optimize trials results damage, decrease neurological disability and improve [76]. Also, systems medicine is going to help in the inte- MS patients’ quality of life. Although several therapeutic gration of biological and clinical knowledge in a more regimens can be proposed, neuroprotective therapy is comprehensive understanding of the disease and patients’ envisioned as combination therapy with other disease heterogeneity, which will pay off by improving our accur- modifying drugs targeting the pathogenic cascade, such acy for transition from preclinical to clinical stages of drug as immunomodulatory therapy in MS. Neuroprotective development [77, 78]. therapies should be started early in the course of the Finally, in order to probe efficacy of neuroprotective disease, because axonal damage start to accumulate from drugs in clinical trials, we need sensitive surrogate and the beginning of the disease. And such therapies may clinical endpoints for the mechanism of action and the extent for the whole life and for almost all types of level of damage. Again, this is critical because many disease, from clinically isolated syndromes to progressive drugs may have failed not due to a lack of efficacy, but MS. In addition to the use of neuroprotective therapies because the incapacity to measure such effects with the for preventing chronic damage in MS, these therapies proposed end-points. The most common proposed surro- would be used for acute neuroprotection at the time gate endpoints is imaging. In the case of MRI, the most patients suffer an acute relapse of MS, NMO or Optic validated marker for MS is presence of new lesions (either Neuritis. However, we need to learn which neuroprotec- contrast enhancing lesions or new lesions in T2), but this tive therapy is more required for each subgroup of marker is useful for immunomodulatory drugs, not for patients to be more effective. To this aim, it is required neuroprotective drugs. Alternatively, brain atrophy is the development of biomarkers of CNS damage processes, best correlate of disability in MS, but brain atrophy is diffi- to be used to select the right drugs at each stage of the cult to measure requiring advanced imaging methods, disease process. This may also help to identify MS sub- prone to high variability between scanners and techniques types with different involvement of CNS damage mecha- and with low sensitivity to changes [79]. For this reason, nisms operating at a given time. Such subtypes may other approaches such as optical coherence tomography overlap with MS pathological subtypes or with genetic offer the opportunity to quantify with high accuracy retina risks, which is unknown at present. Tailoring combin- atrophy [80] and is now being added to phase 2 and 3 ation therapy with immunotherapies using biomarkers clinical trials [81]. Regarding clinical endpoints, clinical would be one of the next challenges for MS therapeutics scales such as the Expanded Disability Status Scale (EDSS) in the medium term that hopefully is going to improve are complex, with high variability and subjectivity and the quality of life of people with MS. with low sensitivity to meaningful clinical changes associ- ated with neuroprotection. For this reason, several new Abbreviations ALS: amiotrophic lateral sclerosis; ATP: adenosin tri-phosphate; BDNF: brain clinical outcomes such as low contrast visual acuity [82] derived nerve factor; CNS: central nervous system; EDSS: expanded disability or activity levels measured with accelerometers [83] are status scale; GSK3: glycogen synthase kinase 3; IKK: inhibitor of kappa B promising avenues for evaluating neuroprotective drugs. kinase; JNK: c-Jun N-terminal kinases; Lingo-1: leucine rich repeat and Villoslada Multiple Sclerosis and Demyelinating Disorders (2016) 1:1 Page 10 of 11 immunoglobin-like domain-containing protein 1; mAb: monoclonal antibody; 19. Segal RA. Selectivity in neurotrophin signaling: theme and variations. Annu MAPKK: mitogen-activated protein kinase kinase; Nerf2: nuclear factor Rev Neurosci. 2003;26:299–330. (erythroid-derived 2)-like 2; NMDA: N-methyl-D-aspartate; MS: multiple 20. Villoslada P, Hauser SL, Bartke I, Unger J, Heald N, Rosenberg D, et al. sclerosis; NMO: neuromyelitis optica; NO: nitric oxide; MRI: magnetic Human nerve growth factor protects common marmosets against resonance imaging; NAA: N-Acetyl- Aspartate; NAD: nicotinamide adenine autoimmune encephalomyelitis by switching the balance of T helper cell dinucleotide; NFKB: nuclear factor-κB; Nogo-A: neurite outgrowth inhibitor A; type 1 and 2 cytokines within the central nervous system. J Exp Med. NMNAT2: nicotinamide nucleotide adenylyltransferase 2; PC: phosphatidilcholine; 2000;191(10):1799–806. PI3K: phosphoinositide 3-kinase; PHR1: phosphate starvation response 1; 21. Colafrancesco V, Villoslada P. Targeting NGF pathway for developing Sarm1: Sterile Alpha And TIR Motif Containing 1. neuroprotective therapies for multiple sclerosis and other neurological diseases. Arch Ital Biol. 2011;149(2):183–92. 22. The BDNF Study Group (Phase III). A controlled trial of recombinant Competing interests methionyl human BDNF in ALS: Neurology. 1999;52(7):1427–33. PV has received consultancy fees from Roche, Novartis and Digna Biotech. 23. ALS CNTF Treatment Study Group. A double-blind placebo-controlled clinical He is founder and advisor of Bionure Inc. and holds patent rights for the use trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) of Methylthioadenosine and BN201 for the treatment of MS and other in amyotrophic lateral sclerosis. Neurology. 1996;46(5):1244–9. neurological diseases. 24. Sorenson EJ, Windbank AJ, Mandrekar JN, Bamlet WR, Appel SH, Armon C, et al. Subcutaneous IGF-1 is not beneficial in 2-year ALS trial. Neurology. Acknowledgement 2008;71(22):1770–5. I would like to thanks Erika Lampert for the English review of the 25. Tuszynski MH, Thal L, Pay M, Salmon DP, U HS, Bakay R, et al. A phase 1 manuscript. 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Neuroprotective therapies for multiple sclerosis and other demyelinating diseases

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Springer Journals
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Copyright © 2016 by Villoslada.
Subject
Psychology; Neuropsychology; Clinical Psychology
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2056-6115
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10.1186/s40893-016-0004-0
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Abstract

Damage to the Central Nervous Systems (CNS) in Multiple Sclerosis (MS) seems to be mainly due to chronic inflammation of the CNS with superimposed bouts of inflammatory activity by the adaptive immune system. The immune mediated damage can be amplified by neurodegenerative mechanisms in damaged axons including anterograde or retrograde axonal or transynaptic degeneration, synaptic pruning and neuronal or oligodendrocyte death. As such, it is highly unlikely that CNS damage can be prevented using only immunomodulatory drugs. For this reason, neuroprotection, aimed at preventing axonal, neuronal, myelin, and oligodendrocyte damage and cell death in the presence of this toxic microenvironment is highly pursued in MS and other demyelinating diseases. Neuroprotective strategies target different processes including oxidative stress, ionic imbalance (sodium, potassium or calcium), energy depletion, trophic factor support, metabolites balance, excitotoxicity, apoptosis, remyelination, etc. Although none of these strategies have translated into approved drugs to date, improvement in the understanding of underlying biology, in the design of clinical trials specific for assessing neuroprotection, and new technologies for developing novel therapies for neuroprotection suggest a new avenue for treating MS, Optic Neuritis or Neuromyelitis Optica (NMO). Several of these therapies are now entering clinical phases and if successful, such strategies would improve patients’ quality of life, and will be even more critical for patients with progressive MS. In the event that such therapies target natural repair mechanisms rather than disease specific processes, they can potentially be useful for other brain diseases such as stroke, neurodegenerative diseases, brain trauma or epilepsy. Keywords: Multiple sclerosis, Neuromyelitis optica, Demyelinating diseases, Neuroprotection, Trophic factors, Axonal damage, Remyelination Background there are significant limitations for promoting neuronal The central nervous system is highly sensitive to damage: network regeneration in adults after damage (e.g. presence the role of neuroprotection of axonal growth inhibitory molecules such as neurite The Central Nervous System (CNS) is especially sensi- outgrowth inhibitor A (Nogo-A)). Nevertheless, even if tive to damage compared to other tissues because of its regenerative therapy for the CNS is highly sought after, an highly specialized structure and function; it is composed intermediate, longer-term promising alternative approach of billions of neurons making both long and short-range is neuroprotection [3]. connections, requires high energy and metabolite con- After insults such as ischemia, inflammation or excito- sumption, and has significant post-damage repair restric- toxicity, neurons and axons may suffer significant damage, tions. Brain connections are made in a highly complex resulting in oxidative damage of DNA and proteins, and synchronized process during development and are reduced energy production, imbalance of ionic homeosta- refined with training [1]. Once defined, brain connectiv- sis and ion channel functioning, endoplasmic reticulum ity is fixed by myelination and other processes in order impairment and protein folding degradation or micro- to preserve memory and function [1, 2]. For this reason, tubule mediated axonal transport impairment. Due to the high level energetic and functional requirements that Correspondence: pvilloslada@clinic.ub.es neurons have for maintaining long-distance nerve conduc- Center of Neuroimmunology, Institut d’Investigacions Biomèdiques August tion (with axons up to 0.5 m long in the corticospinal Pi i Sunyer (IDIBAPS), Centre Cellex 3A, Casanova 145, Barcelona 08036, Spain Department of Neurology, University of California, San Francisco, USA © 2016 Villoslada. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Villoslada Multiple Sclerosis and Demyelinating Disorders (2016) 1:1 Page 2 of 11 tract), neuronal malfunction can trigger self-destruction the release of trophic factors, suppressing local inflamma- processes such as apoptosis, autophagia, synaptic pruning tion or promoting a microenvironment supporting the and many other forms of neuronal cell death [4–6]. survival of neurons, axons and oligodendrocytes [12]. Furthermore, damaged axons can trigger an active process Finally, secondary neuroprotection can be achieved by the of axonal degeneration regulated by levels of nicotinamide reduction of the insult such as restoring blood supply in adenine dinucleotide (NAD). Axonal degeneration is a ischemia, decreasing excitotoxicity by reducing epilepto- process different from apoptosis, which results in acute genic activity in seizures or decreasing CNS inflammation axonal transection and chronic anterograde (Wallerian) or with the use of immunomodulatory drugs (e.g. glatiramer retrograde degeneration. This process is regulated by acetate, fingolimod, dimethyl-fumarate or laquinimod) in several key molecules such as nicotinamide nucleotide the case of MS [13–16]. adenylyltransferase 2 (NMNAT2), Sterile Alpha And TIR Table 1 displays a list of several therapeutic strategies Motif Containing 1 (Sarm1) and phosphate starvation being pursued for neuroprotection. In the pursuit for response 1 (PHR1) which regulates levels of NAD, or neuroprotective strategies, trophic factors are proposed downstream steps regulated by c-Jun N-terminal kinases as the Holy Grail [17, 18]. Rather than coding for all (JNK), glycogen synthase kinase 3 (GSK3) or inhibitor of neuronal connections during development, evolution kappa B kinase (IKK) converging in mitochondria and developed the trophic factor strategy, which regulates energy dysfunction and calpains activation leading to neuronal survival and connection maintenance with the calcium imbalance [7, 8]. Additionally, myelin is highly release of trophic factors from the target cell to the susceptible to damage in the white matter because oligo- projecting neuron. For this reason, trophic factors dendrocytes are also high-energy demanding cells (myelin activate a set of signaling pathways in neurons, such as turn-over is around one month) but the blood supply Phosphoinositide 3-kinase (PI3K), Mitogen-activated prioritizes grey over white matter [6]. Moreover, lipid protein kinase kinase (MAPKK), Nuclear factor-κB structures such as myelin are highly susceptible to damage (NFKB) and others that stop apoptosis, promote cell by immune mediators and oxidative stress [9]. In this survival and differentiation and trigger other beneficial context, inflammatory, ischemic or degenerative insults effects such as decreasing oxidative stress, regulating can induce either direct damage of the neurons (e.g. ne- ion channels, etc. [19]. Several growth factors have been crosis) or delayed degenerative processes that are triggered tested in animal models or clinical trials including neu- once surviving neurons identify they can no longer rotrophins (nerve growth factor, brain-derived nerve maintain their function and initiate different forms of cell factor, neurotrophin-3), insulin-growth factor (IGF-1), death, axonal degeneration or synaptic pruning [10]. neurocytokines (cilliary-neurotrophic factor, leukemia Another feature to take into account when managing inhibitor factor, interleukin-6), and glial-derived nerve neurological damage is the plastic and redundant nature factor family (erythropoietin, etc.) [20, 21]. They were of the CNS, which explain why damage of many CNS tested in trials of peripheral neuropathy (diabetes or regions are not eloquent at the clinical level. This implies adquired immunodeficiency syndrome) or neurodegen- that CNS damage need to surpasse a given threshold of erative diseases (Alzheimer disease, Parkinson disease, damage in order to translate to clinical symptoms, which Huntington disease, Amyotrophic Lateral Sclerosis (ALS)) prevents close monitoring of CNS damage by clinical using human recombinant proteins delivered intraven- assessment and cause delayed diagnosis or disability moni- ously, intrathecaly or using engineered cells or gene ther- toring. All these facts, including sensitivity of neural apy vectors [22–25]. Lack of success to date for the use of networks to damage, poor regenerative ability, and late trophic factors to prevent CNS damage does not preclude diagnosis of CNS damage, support neuroprotection as an the usefulness of trophic factors as a therapeutic target. important therapeutic strategy for decreasing the burden Lack of efficacy was attributed to poor pharmacological of neurological diseases. properties of the recombinant proteins to enter the CNS and reach the target neurons, inadequate clinical trial de- Neuroprotective strategies sign, such as testing patients in late stages when neuronal Almost every mechanism of damage identified in brain death is massive and using insensitive clinical or imaging diseases has been proposed as a therapeutic target for outcomes, or side effects that limited dosing and patient neuroprotection (Fig. 1). Several biological processes exposition [26, 27]. However, the trophic factor pathways specific to the CNS (e.g. trophic factor signaling, axonal are at the core of cellular processes promoting neuronal guidance, myelin formation) or critical for neurons (e.g. and oligodendrocyte survival and for this reason are worth apoptosis, energetic supply, ionic balance) have been pursuing to see if activation of these pathways using differ- mimicked with experimental therapies [3, 11]. In addition, ent strategies might prevent permanent CNS damage. several regenerative therapies, such as stem cells, may pro- Energy depletion and mitochondria dysfunction are vide some benefits via neuroprotective effects, including another key factor in promoting neuronal degeneration Villoslada Multiple Sclerosis and Demyelinating Disorders (2016) 1:1 Page 3 of 11 Fig. 1 Proposed targets for neuroprotective therapies. The pathways involved in neuroprotection include 1) Active axonal degeneration pathway activation (mediated by depletion of NAD levels by NMNAT2, PHR1 and Sarm1 activation); 2) trophic factor signaling (PI3K, MAPKK, NFkB); 3) oxidative stress (induced by inflammatory cells and mitochondria dysfunction); 4) energy depletion (due to mitochondria impairment and increased demand from Ca channels); 5) axonal transport blockade (failing to deliver mitochondria, signaling and molecular complexes to soma, nodes of Ranvier or synpasis); 6) ionic imbalance (due to ion channel redistribution and changes in activity, leading to increase of intracellular calcium); 7) Excitotoxicity (mediated by excess of glutamate signaling through the NMDA receptors); 8) remyelination (from OPC repopulation of demyelinated areas to myelination of denuded axons by mature oligodendrocytes (OG), which provide metabolic support to the axon (NAA or PC); 9) protective effects of astrocytes (providing trophic factors such as IGF-1 or BDNF, metabolic substrates such as lactate, or pro-survival signals such as CD200-CD200L) and M2 microglia (with scavenger and tissue healing activity) Table 1 Molecules and pathways targeted in neuroprotection Pathway Molecule Candidate drugs Trophic factors BDNF, IGF-1, CNTF, etc. rhBNDF, rhIGF-1, rhCNTF, etc., CERE-110 (AAV2-NGF) Mitochondria dysfunction and Cytochrome C, ATP Resveratrol, Rosiglitazone, Pioglitazone, Troglitazone, energy depletion Bezafibrate (PPARγ activator) Ion channel Sodium, Potassium or Calcium channels, Phenitoin, Lamotrigin, Amiloride Acid-Sensing Ion Channels Oxidative stress iNOS, Nerf2 Dimethyl-Fumarate, Resveratrol, Vitamin E, Vitamin C, Melatonin, Carnosine, Coenzyme-Q, Idebenone, Carotenoids Excitotoxicity Glutamate Memantine, Riluzole Demyelination MOG, Lingo-1 BIIB003, Clemastine benztropine, miconazole and clobetasol Axonal transport Dynamin, kinesin, microtubules Epothilone B Inhibitory molecules axonal growth Lingo-1, Nogo-A BIIB003, GSK1223249 and myelination Apoptosis Bcl2, Bim, Bax, Cytochrome C, Caspase-3 Caspase or calpain inhibitors, Mynocycline Microglia M2 mediated neuroprotection CD200, trophic factors (BDNF), Interferon-beta, Glatiramer acetate, Fumarate, anti-inflammatory cytokines (IL-4, IL-10, TGFß) Dimethyl-Fumarate, Mesenchymal stem cells Astrocyte mediated neuroprotection Trophic factors, NAA, pyruvate, lactate Pentamidine, Methylthioadenosine, Fingolimod BDNF brain-derived nerve factor, IGF-1 insulin growth factor, CNTF cilliary neurotrophic factor, NGF Nerve growth factor, rh recombinant human, iNOS inducible nitric oxide synthase, ATP adenosine triphosphate, MOG myelin oligodendrocyte glycoprotein, NAA N-Acetyl aspartate Villoslada Multiple Sclerosis and Demyelinating Disorders (2016) 1:1 Page 4 of 11 [4, 28, 29]. The CNS consumes 20 % of the overall to modulate without inducing further damage. However, oxygen and energy of the body and neurons require the several approved therapies reduce oxidative stress in- support of astrocytes for maintaining their metabolic duced by the insult such as the immunomodulatory drug activity [6]. Neurons use lactate as a substrate for the dimethyl-fumarate (through activation of nuclear factor Krebs cycle, which is provided by astrocytes. Neurons (erythroid-derived 2)-like 2 (Nerf2)) [39], and mesenchy- are very sensitive to adenosine triphosphate (ATP) de- mal stem cells [40], which decrease reactive oxygen pletion and mitochondrial damage due to their high- species induced by inflammation. energy consumption needed to maintain the intensive Excitotoxicity is postulated as the prime mechanism of protein systems supporting their connections as well as damage in epilepsy and it has also been associated with the ion channels in charge of maintaining the electrical neurodegenerative diseases as well with MS [41, 42]. By impulse. This is particularly true for axons, because they over-activating the excitatory glutamate receptors, neu- are long and tiny structures receiving support from the rons experience high levels of electrical and energetic soma as well as from the axon-myelin unit [4]. Energy activity, inducing ion imbalance and promoting neuronal depletion, mitochondria function impairment and axonal death. Although there is clear evidence about the role of transport deficits are common in CNS diseases and for this process in animal models, its involvement in MS this reason targeting energy supply to the CNS has and other brain diseases has not been clarified in detail. been pursued as well. Studies began by providing add- Riluzole is an approved drug inhibiting N-methyl-D- itional sugar supplies or decreasing metabolic rate (e.g. aspartate (NMDA) receptors, in addition to modulat- hypothermia) but now other strategies such as adminis- ing sodium channels, but its efficacy in ALS is modest tering metabolite precursors, or preserving mitochon- and trials in MS failed to show benefits [43]. Memantine dria functioning have also been tested in trials [29–31]. is approved for Alzheimer’s disease and was shown to There is now a strong interest in understanding the modulate glutamate excitatory activation [44], but it was early molecular events in mitochondria damage during found to transiently worsen symptoms in patients with neuronal and axonal damage in order to prevent ener- MS, reproducing pseudoexacerbations [45, 46]. getic failure [4, 7, 32]. Demyelination is the most prominent feature in MS. Ion channels are key for neuronal homeostasis and for Promoting myelin recovery through remyelination is a maintaining the electrical impulse. Due to the highly natural strategy for treating demyelinating diseases. It is specialized neuronal design, ion channel activity is highly important to keep in mind that myelin is one of the prominent in the axonal initial segment as well as at the most important elements for protecting axons, the node of Ranvier [33]. This creates specific sites where myelin-axon unit [9]. Myelin is active not only in pro- ion fluxes are modulated and energy is required for axon moting saltatory conduction (which increases electrical functioning. Ion channel modulators have been explored conduction speed and reduces energy needs), but also as neuroprotective therapies in addition to their known in providing metabolic support to axons (e.g. N-Acetyl- beneficial effects in epilepsy or pain, including sodium Aspartate (NAA), phosphatidylcholine (PC), etc.) [47]. channel modulators phenytoin, carbamacepin, lamotri- For this reason, preventing demyelination and promot- gine, amiloride; and potassium channel modulators, ing remyelination is one of the most important neuro- aminopyridine or diazoxide (Table 2) [33]. Although protective strategies for MS [48]. There are several benefits has been observed in animal models and drugs being tested at present to promote remyelination small clinical trials, the challenge is determining how by blocking leucine rich repeat and immunoglobin-like to maintain their beneficial effects in the long-term domain-containing protein 1 (Lingo-1) using anti-Lingo-1 and understanding to which degree their effects are monoclonal antibody, or repurposing drugs such as clem- just maintaining the electrical impulse (symptomatic astine or guanabenz (Table 2). The main challenge will be effects) versus promoting long-term neuronal or axonal to probe in humans whether such drugs are able to induce survival (neuroprotection effects) [34]. remyelination of the CNS and whether this biological Oxidative stress is another hot topic in neuroprotec- activity translates to clinical benefits. Quantifying demye- tion [35]. The concept that free radicals degrade DNA lination and remyelination in the living human CNS still and proteins suggest that anti-oxidative strategies would remains a challenge at the clinical level due to techno- prevent cell death. There is ample evidence of the pres- logical limitations (e.g. lack of specificity of MRI se- ence of increased oxidative stress in the damaged CNS quences such as magnetic transfer ratio) [49]. in MS, neurodegenerative diseases, stroke and epilepsy Axonal transport is a key process in the homeostasis [36–38]. However, oxidation in mitochondria and other of neurons and their long connections. Axons need to organelles is a complex process required for energy transport to the synapsis most of the protein synthesis production and other metabolic activities (e.g. signaling machinery as well as providing energy supply to the by nitric oxide (NO)) and for this reason is very difficult nodes of Ranvier and synapsis. In addition trophic factor Villoslada Multiple Sclerosis and Demyelinating Disorders (2016) 1:1 Page 5 of 11 Table 2 Neuroprotective drugs in clinical development for MS Drug Company Type of compound MoA summary Route of Phase CT.org administration KPT-350 Karyopharm Therapeutic Small molecule - Selective Inhibitor Antioxidant Neuroprotection Oral Preclinical N/A of Nuclear Export (SINE) NDC-1308 ENDECE Neural Small molecule Estradiol analog Neuroprotection Remyelination N/A Preclinical N/A Methylthioadenosine Digna Biotech Metabolite Methyltransferases modulator Neuroprotection Oral Preclinical N/A Remyelination NRP2945 CuroNZ Peptide Neuroprotection N/A Preclinical N/A ER agonist Karo Bio AB Smal chemicals Estrogen Receptor beta agonist Neuroprotection N/A Preclinical N/A VX15/2503 Vaccinex mAb - anti-semaphorin 4D Anti-SEMA4D Neuroprotection Remyelination Intravenous Phase 1 NCT01764737 RNS60 Revalesio Physically-Modified Saline Immunomodulation Neuroprotection Intravenous Phase 2 NCT01714089 GNbAC1 GeNeuro mAb First-in-Class Immunomodulation Remyelination Intravenous Phase 2a NCT01639300 TRO19622 Olesoxime Trophos SA Small chemical Antioxidant Oral Phase 1 NCT01808885 BIIB0033 - Anti-LINGO1 Biogen Idec mAb LINGO-1 antagonist Remyelination Intravenous Phase 2 NCT01864148 Neuroprotection Phase 2 NCT01721161 rHIgM22 Acorda Therapeutics mAb - Recombinant human IgM Remyelination Intravenous Phase 1 NCT01803867 MN-166 Ibudilast MediciNova Small molecule Immunomodulation Neuroprotection Oral Phase 2 NCT01982942 RGN-352 RegeneRx Peptide Neuroprotection Remyelination N/A N/A N/A EGCG - Epigallocatechin-gallate Generic Green tea extract (Polyphenon E) Anti-oxidant Oral Phase 2 NCT00525668 NCT01451723 Lamotrigine GlaxoSmithKline Small chemical Sodium channel modulator Neuroprotection Oral Oral NCT01879527 Phenitoin Generic Small chemical Sodium channel modulator Neuroprotection Oral Phase 2 NCT01451593 MRF-008 Guanabenz Myelin Repair Small chemical Alpha agonist of the alpha-2 adrenergic receptor Oral Phase 1 NCT02423083 Foundation Remyelination Clemastine Generic Small chemical Remyelination Oral Phase 2 NCT02040298 BAF312 Novartis Small chemical - Siponimod S1P1 antagonist Neuroprotection Oral Phase 2 NCT00879658 RRMS Phase 3 SPMS Amiloride Generic Small chemical Sodium channel modulator Oral Phase 2 NCT01910259 BN201 Bionure Small chemical Neurotrophin agonist Neuroprotection Intravenous Phase 1 N/A Erythropietin Generic Human recombinant protein Trophic factor Neuroprotection Intravenous Phase 3 NCT01962571 GSK1223249 – Ozanezumab GlaxoSmithKline mAb Anti-Nogo-A Axonal regeneration Intravenous Phase 2 NCT01435993 Diazoxide Generic Small chemical Potassium channel opener & mitochondrial Oral Phase 2 NCT01428726 channel modulator Minocycline Generic Small chemical Anti-apoptotic & anti-oxidant Oral Phase 2 NCT01073813 Riluzole Generic Small chemical Sodium channel and NMDA modulator Oral Phase 2 NCT00501943 Villoslada Multiple Sclerosis and Demyelinating Disorders (2016) 1:1 Page 6 of 11 Table 2 Neuroprotective drugs in clinical development for MS (Continued) MD1003 - Biotin Generic Vitamin Carboxylases coenzyme (acetylCoA carboxylase) Oral Phase 3 NCT02220933 Remyelination BG12 - Dimethyl Fumarate Biogen Idec Metabolite Anti-oxidant hydroxycarboxylic acid receptor 2 Oral Approved NCT00420212 agonist FTY720 - Fingolimod Novartis Small chemical S1P1 and S1P5 antagonist neuroprotection Oral Approved NCT00355134 Villoslada Multiple Sclerosis and Demyelinating Disorders (2016) 1:1 Page 7 of 11 transportation (e.g. brain-derived neurotrophic factor also termed M2, is associated with suppressing inflam- (BDNF)) from synapsis to the soma is also critical for mation and the creation of a supportive microenviron- neuronal survival [29]. This requires efficient transport ment supporting neuronal survival [12]. Furthermore, through the axons based on intraxonal fluxes but mainly astrocytes, as the main supporters of neuronal function, driven by microtubules transporting organelles to and display a wide array of positive functions for promoting from the soma using the dynein and kinesin systems re- neuronal survival. Moreover, stem cell therapy may show spectively. Such molecular transporters are very sensitive beneficial effects above and beyond just replacing cells to protein denaturation, lack of energy, inflammation by creating a supportive microenvironment and suppress- and other types of damage [32, 50]. Also, it is known ing inflammation [12, 40]. Identification of the different that mitochondria accumulate in the nodes of Ranvier mechanisms involved will provide new targets for devel- (stationary sites) in order to provide extra ATP to sites oping neuroprotective strategies. rich in ion channels, and they are also transported to synapses to provide energy and are retrogradely trans- Unmet needs for neuroprotection in MS and ported for degradation. Inflammation, ischemia and other demyelinating diseases processes severely impair axonal transportation, including In MS, CNS damage is produced by a complex inflam- mitochondria delivery at nodes of Ranvier, contributing matory process. Although in the past it was believed that to energy and metabolite depletion and axonal damage in the relapsing-remitting phase CNS damage was due [32, 51]. Recently, it has been shown that tubuline tar- only to the presence of inflammatory infiltrates within geting drugs may preserve microtubule function and the MS plaques, in the last decade it has been clearly protect axons from degradation in models of spinal shown that MS is a diffuse disease with inflammation, cord injury [52]. In addition, neurofilaments are in demyelination and axonal loss both in the grey and charge of keeping the 3D axonal structure and after white matter [58, 59]. This diffuse inflammation, also damage, neurofilaments become hyperphosphorylated, termed trapped inflammation, is mainly drive by activated losing their function and inducing the collapse of axons microglia, although cells of the adaptive immune system [53]. Therefore, preserving axonal structure and function may be also present. Therefore, myelin and axons are is an important strategy for promoting neuroprotection. acutely damaged by inflammatory infiltrates and chronic- For more than a century, since Cajal seminal studies, ally damaged by chronic microglia activation; both pro- it has been known that the brain inhibits axonal regrowth, cesses being present in relapsing and progressive MS to which prevents CNS regeneration. The identification that different extent and dynamics [36]. However, in progres- myelin was the main inhibitor of axonal growth was sive MS, relapses due to new inflammatory infiltrates tend followed by the identification of several proteins such as to decrease or disappear because less tissue is available for Lingo-1 and Nogo-A that prevent axonal growth signaling damage. Also, in parallel to the inflammatory process, NGF through the nerve growth factor (NGF) receptor p75 axonal degeneration takes place in CNS areas already receptor [54]. This mechanism is important for avoiding damaged long time ago because of the lack of myelin the formation of aberrant connections and preserving support, presence of an aggressive microenvironment, brain connectivity, at the cost of decreasing the regenera- retrograde axonal degeneration or transynaptic degener- tive capacity of the CNS. The discovery of the molecules ation [60]. Moreover, after one decade of damage and responsible for such processes has been followed by the recovery during the relapsing-remittig phase, oligodendro- development of monoclonal antibodies (mAb) targeting cytes fail to produce new myelin and ultimately die; with these pathways in order to promote axonal regeneration. time, the capacity of oligodendrocyte precursors to replace There are several clinical trials in MS testing such ap- lost oligodendrocytes also decreases, leading to large areas proaches including the use of mAb against Lingo-1 and of demyelination [61]. In this scenario, it is clear that MS Nogo-A (Table 2). The main concern is the pharmaco- patients require therapies aimed at stopping the degenera- logical restrictions that mAb has in order to reach high tive process and preventing new CNS damage, on top of levels in the CNS as well as the timing for this therapeutic the immunomodulatory strategy aimed at preventing intervention after injury. inflammation [62]. Finally, it is well known that glia, including astrocytes Current immunomodulatory drugs are not completely and microglia, can display neuroprotective activities, effective and drugs with high efficacy may induce severe although many of them are poorly understood [12, 55]. adverse-events. We must also take into account patient For example, healthy neurons express CD200, which heterogeneity as well as the difficulty for predicting interacts with CD200L promoting survival signals [56]. disease activity at the time of defining the immunomod- Also, both microglia and astrocytes can release trophic ulatory therapy. For this reason, at present is not factors and provide metabolic support to neuronal func- possible to guarantee that treated patients are going to tion [57]. The neuroprotective phenotype of microglia, be free of disease activity and CNS damage induced by Villoslada Multiple Sclerosis and Demyelinating Disorders (2016) 1:1 Page 8 of 11 the autoimmune attack. And even in the best scenario, humans with remyelinating potential [68] and it is now be- damaged tissue is still at risk of developing degenerative ing tested in clinical trials in MS patients (NCT01803867, processes in the long-term. Considering that regenera- NCT02398461). Regarding small chemicals, two approved tive therapies are still far from being applied in clinical drugs that are being explored for their effect on remyelina- practice, protecting the brain against chronic inflamma- tion are clemastine and guanabenz after having shown a tion (not significantly modulated by current immunother- remyelinating effect in vitro and animal models [69]. apy), and preventing neurodegeneration in the long-term, Other strategies in clinical phases include the use of is being pursued as the main strategy in the medium term trophic factor compounds (eritropoietin, BN201), anti- for decreasing disability accumulation in patients with oxidant compounds (the green tea extract epigallocatechin- MS. This is true both for patients with relapsing MS as 3-gallate, ginkgo biloba extracts, biotin, dimethyl-fumarate, well as in the case of patients with progressive MS, in olexosime), modulating estrogen receptors, metabo- which inflammation is still present until the end and lites (dimethyl-fumarate, methyltioadenosine), blocking degenerative processes [55, 59]. semaphorins (VX15/2503), and ion channels modula- In the case of other demyelinating diseases such as tors (carbamacepin, phenytoin, lamotrigin, amiloride, NMO, the need for neuroprotection is also present but riluzole) (Table 2) [21, 70]. All these drugs still need for different reasons [63]. In NMO there is no evidence to show their efficacy in phase 3 trials and then define of progressive course of the disease or presence of how they would be integrated in the MS armamentarium, chronic trapped inflammation in the CNS. For this probably as a combination therapy with immunomodula- reason, all CNS damage and clinical disability observed tors for relapsing MS or perhaps in combination with in NMO is attributed to the damage induced during different agents for progressive MS. acute relapses, which are significantly more tissue destruc- In addition to drugs being tested as neuroprotectants, tive than in MS [64]. The necrotic characteristic of the we must also consider stem cells as another approach NMO lesions has parallelism with stroke-induced damage, to neuroprotection in MS [71]. At present, the most a prototypic model for neuroprotection in which is critical tested stem cells are mesenchymal stem cells, which preventing severe CNS damage in order to reduce disabil- have shown immunomodulatory and neuroprotective ity. The good news is that the inflammatory-induced properties in vitro and in animal models [72]. Recent damage in NMO may operate over longer periods of trials in patients with relapsing and progressive MS time than brain ischemia, providing a wider therapeutic have shown some beneficial effects in terms of decreasing window for intervention (from minutes to days). Recur- relapse rate or disability [73–75], but without clarifying rent Idiopatic Optic Neuritis, Relapsing Optic Neuritis whether these effects are due to its immunomodulatory or or Transverse Myelitis are also other less common neuroprotective effects. A large multicentric randomized types of demyelinating diseases that would follow the trial (MESEMS trial; NCT02403947) is ongoing to evalu- NMO paradigm for neuroprotection, decreasing CNS ate its efficacy in MS. In addition, phase 1 and 2 trials are damage due to relapses. ongoing or being planned to test the efficacy of other stem cells such as oligodendrocyte or olfactory ensheeting glial Neuroprotective therapies under development for cells and probably neural cells in the near future. MS and other demyelinating diseases Neuroprotection is a well-accepted concept in the thera- Challenges for developing neuroprotective peutic strategy of neurologists, but in order to be useful therapies at the clinical level, efficacy must be demonstrated in Lack of approved neuroprotective drugs is due to both randomized clinical trials [65, 66]. At present there is a poor understanding of the mechanisms of damage and growing list of new drugs and repurposing of drugs the low recovery ability of the CNS (as discussed above) being tested from phase 1 to phase 3 trials (Table 2). as well as the limitations of clinical trials for probing the One of the most active areas of research are remyelinat- efficacy of such drugs. First, probing the efficacy of a ing therapies, which can be categorized either as regenera- neuroprotective drug requires selecting the right indica- tive therapy (aimed to restore myelin) or neuroprotective tion, stage of the disease and group of patients in which therapy (aimed to protect axons and restore nerve con- such intervention can translate to a biological benefit as duction) [67]. A recent trial testing the mAb blocking well as to a clinical benefit. For example, treating pa- Lingo-1 (BIIB033) has shown improvement in the laten- tients in the very late stages of the disease, when damage cies of the visual evoked potentials in patients with optic of the CNS is very severe and few neurons and axons neuritis, suggesting an improvement of nerve conduction can be rescued, may not translate to clinical benefits. typically associated with remyelination (NCT01721161). This late diagnosis is one of the greatest limitations to date Another mAb promoting remyelination is rHIgM22, which in other neurodegenerative diseases such as Alzheimer or was discovered as part of the natural antibody repertoire in Parkinson disease and probably in progressive MS. Villoslada Multiple Sclerosis and Demyelinating Disorders (2016) 1:1 Page 9 of 11 Second, pharmacological properties of the drug should Conclusions be good enough to be sure to deliver the signal in the Relapsing MS and other demyelinating diseases have right site of the CNS and with enough intensity to ob- benefited significantly from the advancements of new tain positive outcomes. This is one of the limitations of immunomodulatory therapies, but the challenge of mAb, stem cells and some other drugs. Also, dose selec- protecting CNS from damage remains one of the top tion and defining the therapeutic window based in priorities for all demyelinating diseases as well as efficacy-toxicity balance as well as in the timing of the neurodegenerative diseases or acute brain damage by intervention from the onset of damage is critical as well. trauma or stroke. Novel discoveries in neurobiology Previous studies with recombinant trophic factors may provide new therapeutic targets, and new imaging modal- have failed because poor pharmacokinetic properties as ities provide the opportunity to evaluate the efficacy of well as toxicity of the recombinant proteins prevented these new neuroprotective drugs. Because several of the the use of efficacious doses [27]. Also, we must keep in mechanisms being targeted by neuroprotective therapies mind that patients with MS are young and the disease are common between diseases, some of the biomarkers evolves slowly over years, and for this reason MS patients and therapeutics strategies may be useful for different type are not likely to accept the risk of side-effects. of diseases, although medicine use to tell us that any Third, biomarkers are envisioned as a key strategy for single therapeutic approach fitting all CNS diseases is moving new drugs from preclinical stages to phase 1 highly unlikely. and 2 trials, helping to select the best therapeutic regi- We will hopefully soon have effective neuroprotective men and dose, identify the best patient subgroups to be therapies ready to use in patients, which combined with tested (avoiding non-responders) and match surrogate immunomodulatory drugs, will help to prevent CNS with clinical endpoints in order to optimize trials results damage, decrease neurological disability and improve [76]. Also, systems medicine is going to help in the inte- MS patients’ quality of life. Although several therapeutic gration of biological and clinical knowledge in a more regimens can be proposed, neuroprotective therapy is comprehensive understanding of the disease and patients’ envisioned as combination therapy with other disease heterogeneity, which will pay off by improving our accur- modifying drugs targeting the pathogenic cascade, such acy for transition from preclinical to clinical stages of drug as immunomodulatory therapy in MS. Neuroprotective development [77, 78]. therapies should be started early in the course of the Finally, in order to probe efficacy of neuroprotective disease, because axonal damage start to accumulate from drugs in clinical trials, we need sensitive surrogate and the beginning of the disease. And such therapies may clinical endpoints for the mechanism of action and the extent for the whole life and for almost all types of level of damage. Again, this is critical because many disease, from clinically isolated syndromes to progressive drugs may have failed not due to a lack of efficacy, but MS. In addition to the use of neuroprotective therapies because the incapacity to measure such effects with the for preventing chronic damage in MS, these therapies proposed end-points. The most common proposed surro- would be used for acute neuroprotection at the time gate endpoints is imaging. In the case of MRI, the most patients suffer an acute relapse of MS, NMO or Optic validated marker for MS is presence of new lesions (either Neuritis. However, we need to learn which neuroprotec- contrast enhancing lesions or new lesions in T2), but this tive therapy is more required for each subgroup of marker is useful for immunomodulatory drugs, not for patients to be more effective. To this aim, it is required neuroprotective drugs. Alternatively, brain atrophy is the development of biomarkers of CNS damage processes, best correlate of disability in MS, but brain atrophy is diffi- to be used to select the right drugs at each stage of the cult to measure requiring advanced imaging methods, disease process. This may also help to identify MS sub- prone to high variability between scanners and techniques types with different involvement of CNS damage mecha- and with low sensitivity to changes [79]. For this reason, nisms operating at a given time. Such subtypes may other approaches such as optical coherence tomography overlap with MS pathological subtypes or with genetic offer the opportunity to quantify with high accuracy retina risks, which is unknown at present. Tailoring combin- atrophy [80] and is now being added to phase 2 and 3 ation therapy with immunotherapies using biomarkers clinical trials [81]. Regarding clinical endpoints, clinical would be one of the next challenges for MS therapeutics scales such as the Expanded Disability Status Scale (EDSS) in the medium term that hopefully is going to improve are complex, with high variability and subjectivity and the quality of life of people with MS. with low sensitivity to meaningful clinical changes associ- ated with neuroprotection. For this reason, several new Abbreviations ALS: amiotrophic lateral sclerosis; ATP: adenosin tri-phosphate; BDNF: brain clinical outcomes such as low contrast visual acuity [82] derived nerve factor; CNS: central nervous system; EDSS: expanded disability or activity levels measured with accelerometers [83] are status scale; GSK3: glycogen synthase kinase 3; IKK: inhibitor of kappa B promising avenues for evaluating neuroprotective drugs. kinase; JNK: c-Jun N-terminal kinases; Lingo-1: leucine rich repeat and Villoslada Multiple Sclerosis and Demyelinating Disorders (2016) 1:1 Page 10 of 11 immunoglobin-like domain-containing protein 1; mAb: monoclonal antibody; 19. Segal RA. Selectivity in neurotrophin signaling: theme and variations. Annu MAPKK: mitogen-activated protein kinase kinase; Nerf2: nuclear factor Rev Neurosci. 2003;26:299–330. (erythroid-derived 2)-like 2; NMDA: N-methyl-D-aspartate; MS: multiple 20. Villoslada P, Hauser SL, Bartke I, Unger J, Heald N, Rosenberg D, et al. sclerosis; NMO: neuromyelitis optica; NO: nitric oxide; MRI: magnetic Human nerve growth factor protects common marmosets against resonance imaging; NAA: N-Acetyl- Aspartate; NAD: nicotinamide adenine autoimmune encephalomyelitis by switching the balance of T helper cell dinucleotide; NFKB: nuclear factor-κB; Nogo-A: neurite outgrowth inhibitor A; type 1 and 2 cytokines within the central nervous system. J Exp Med. NMNAT2: nicotinamide nucleotide adenylyltransferase 2; PC: phosphatidilcholine; 2000;191(10):1799–806. PI3K: phosphoinositide 3-kinase; PHR1: phosphate starvation response 1; 21. Colafrancesco V, Villoslada P. Targeting NGF pathway for developing Sarm1: Sterile Alpha And TIR Motif Containing 1. neuroprotective therapies for multiple sclerosis and other neurological diseases. Arch Ital Biol. 2011;149(2):183–92. 22. The BDNF Study Group (Phase III). A controlled trial of recombinant Competing interests methionyl human BDNF in ALS: Neurology. 1999;52(7):1427–33. PV has received consultancy fees from Roche, Novartis and Digna Biotech. 23. ALS CNTF Treatment Study Group. A double-blind placebo-controlled clinical He is founder and advisor of Bionure Inc. and holds patent rights for the use trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) of Methylthioadenosine and BN201 for the treatment of MS and other in amyotrophic lateral sclerosis. Neurology. 1996;46(5):1244–9. neurological diseases. 24. Sorenson EJ, Windbank AJ, Mandrekar JN, Bamlet WR, Appel SH, Armon C, et al. Subcutaneous IGF-1 is not beneficial in 2-year ALS trial. Neurology. Acknowledgement 2008;71(22):1770–5. I would like to thanks Erika Lampert for the English review of the 25. Tuszynski MH, Thal L, Pay M, Salmon DP, U HS, Bakay R, et al. A phase 1 manuscript. 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Multiple Sclerosis and Demyelinating DisordersSpringer Journals

Published: Apr 1, 2016

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